Antithrombotic effects of a platelet fibrinogen receptor antagonist in a canine model of carotid artery thrombosis.

Abstract

Background and Purpose: Platelet-fibrin thrombi in the lumen of atherostenotic carotid arteries may underlie transient ischemic attacks and cerebral infarction. For this reason, we investigated the antiplatelet and antithrombotic effects of a novel and potent platelet fibrinogen receptor (glycoprotein Ilb/lIIa) antagonist (SK&F 106760).Methods: The effects of 0.1-3.0 mg/kg i.v. SK&F 106760 on platelet aggregation were examined ex vivo in canine platelet-rich plasma (n=20). In addition, the antithrombotic effects of SK&F 106760 were compared with those of aspirin in an acute canine model of extracranial carotid artery thrombosis with high-grade stenosis. Sham-operated (n=4), vehicle-treated (n=6), SK&F 106760-treated (n=8), aspirintreated (n=9), and SK&F 106760+aspirin-treated (n=5) dogs were examined.Results: The intravenous administration of SK&F 106760 caused a dose-related inhibition of ex vivo platelet aggregation. In the carotid artery thrombosis model, an occlusive thrombus formed at stenotic sites in the region of the carotid bifurcation. The thrombogenic process caused a progressive reduction in carotid blood flow and reduced the cortical microvascular perfusion and electroencephalographic power. Based on nuclear magnetic resonance spectroscopy, the occlusive events depleted the stores of high-energy phosphates (adenosine triphosphate and phosphocreatine) and increased the lactate concentration in the forelimb somatosensory area of the parietal cortex. In this model, the administration of 1 mg/kg i.v. SK&F 106760 prevented thrombosis of the stenotic carotid artery. Consequently, neurophysiological, cerebral hemodynamic, and metabolic parameters were all improved significantly in the SK&F 106760-treated group. No dog receiving SK&F 106760 reoccluded during the 1-hour posttreatment observation period. In contrast, thrombosis of the carotid artery was associated with neurophysiological deterioration in six of the nine dogs treated with S mg/kg i.v. aspirin. Both spontaneous and evoked (increased carotid stenosis) aspirin-resistant thrombosis were abolished by SK&F 106760 treatment Conclusions: These results suggest that antagonism of fibrinogen binding to platelet glycoprotein Ilb/IIIa (the final common pathway for aggregation) may represent a new and more effective antithrombotic approach to the treatment of cerebral transient ischemic attacks and infarction associated with extracranial carotid artery disease. (Stroke 1992^3:703-711)

Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation.

“…However, to date, their usefulness in this setting has been suggested only by indirect experiments. In dogs, GP IIb/IIIa blockade prevents local thrombosis in a carotid injury model and improves carotid blood flow, cortical perfusion, and EEG tracings (29). An important ancillary observation in this study was that the use of a GP IIb/IIIa antagonist did not result in a significant increase in intracerebral hemorrhage at doses that exhibited clinical efficacy (1 and 5 mg/kg), which is an important characteristic to be sought in any agent designed to treat stroke.…”

“…Although platelet inhibition has shown some efficacy in the primary prevention of stroke (28), the effectiveness of GP IIb/IIIa antagonism has not been reported in either primary prevention of stroke or in the treatment of acute stroke in progress. Because GP IIb/IIIa antagonism is effective to prevent local thrombosis in a canine carotid injury model (29) and to reduce plateletmediated cyclical blood flow reductions in a primate carotid thrombosis/endothelial injury model (30), we hypothesized that it may also be effective to inhibit microvascular thrombosis, which occurs distal to the obstruction site of a major cerebrovascular arterial tributary. The data in this paper demonstrate that GPI 562 is effective at reducing thrombosis in this distal vascular territory.…”

Effects of Acetylsalicylic Acid on Inhibition of Ex Vivo Platelet Aggregation and Secretion by SKF 107260, a Novel GPIIb/IIIa Receptor Antagonist

“…RGD peptides, including SKF 106760 and SKF 107260, have been effective in abolishing cyclic reductions in blood flow produced in endothelial-damaged coronary arteries with high grade stenoses, even in animals in which aspirin (ASA) had failed (5). Additionally, SKF 106760 has been efficacious in experimental models for the prevention of myocardial infarction, as an adjunct to thrombolysis, and for the prevention of stroke and transient cerebral ischemia (6,7). SKF 107260, a competitive antagonist of the platelet GPII!IIIa receptor, has a K; of approximately 2.4 nM for inhibition of fibrinogen binding to the purified human GPIIb!IIIa receptor.…”

Recombinant leech antiplatelet protein prevents collagen-mediated platelet aggregation but not collagen graft thrombosis in baboons.

“…13 The relative contributions of the individual components in this process remain unclear; however, the recent identification and characterization of potent and specific inhibitors of coagulation proteins and platelet activation have advanced knowledge in this area. For example, the pivotal role of the platelet fibrinogen receptor glycoprotein (GP) Ilb/IIIa (GPIIb/IIIa) in arterial thrombosis has been well established in canine 4 - 6 and nonhuman primate 7 ' 8 models of thrombosis using selective antagonists of this receptor. Using the direct thrombin inhibitor recombinant hirudin 9 -12 and agents that limit thrombin generation, such as activated protein C, 13 factor Xa inhibitors, 14-' 6 and tissue factor pathway inhibitor, 17 thrombin has been identified as a key clotting factor involved in the promotion of arterial thrombogenesis.…”